Afatinib is a multi-target small molecule drug researched and developed by German Boehringer Ingelheim. It is an irreversible inhibitor of epidermal growth factor receptor (EGFR) and human epidermal receptor (HER2) tyrosine kinase, and also the first drug for lung cancer when failure by the treatment of EGFR inhibitor. Clinically Afatinib can be used for treatment of advanced non-small cell lung cancer and advanced breast cancer, and intestinal cancer. This drug was approved to appear on the markets by US FDA and European EMEA on Jul. 12, 2013 and Sep. 25, 2013 respectively through US FDA Fast Track, which is applicable for first-line treatment of the advanced non-small cell lung cancer (NSCLC) and HER2-positive advanced breast cancer patients. Its trade names are Gilotrif (United States) and Giotrif (EU) respectively.
The chemical name of Afatinib (I) is 4-[(3-chloro-4-fluorophenyl) amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl] amino}-7-[(S)-(tetrahydrofuran-3-yl) oxy] quinazoline.

The global patent No. WO0250043A1 and No. WO03094921A2 for original research of Boehringer Ingelheim reported the preparation method of Afatinib: using parent nucleus 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-fluoro-quinazoline (XII) as a starting material, substitution reaction with S-3-hydroxy-tetrahydrofuran occurs under the catalyzation of potassium tert-butoxide, to produce 4-[(3-chloro-4-fluorophenyl) amino]-6-nitro-7-[(S)-(tetrahydrofuran-3-yl) oxy] quinazoline (XIII); after 6-position nitro-reduction, get the corresponding amide (XIV) which reacts with bromo-crotonyl chloride to get the intermediate (XV) through amidation reaction. After amination reaction between intermediate (XV) and dimethylamine, get Afatinib (I).

This shows that the key of Afatinib preparation technology is the structural design of quinazoline nucleus and the selection of cyclization time. Currently, the preparation method of Afatinib is to modify the functional group at 7- and 6-position sequentially through 4-position functionalized quinazoline nucleus (XII). This method should firstly prepare the quinazoline nucleus, then transformation of side chain functional group, thus it includes multiple steps, with a low total yield; moreover, column chromatography is necessary used for separation and purification in many steps, thus, it is not applicable for industrialization.